Process for obtaining organic amino diols



Patented July 1, 1950 UNITED STATES PATENT OFFICE PROCESS FOR 08 AMINOTAININ G ORGANIC DIOLS George W. Moersch Allen C. Moore, Detroit, Michaesignors to Parke, Davis & Company, Detroit, Mich., a corporation ofMichigan No Drawing. Application December 21, 1948,

Serial No. 66,594 g This invention relates to a process for the pro-,

duction of organic amino diols and acid addition R; on N'H-Rs- K-CHaORlwhere Y is hydrogen or a-NO: group, R1 and Re are the same or difl'erentand represent hydrogen, halogen, lower alkyl or lower alkoxy radicals,R: is hydrogen or a lower alkyl radical and R4 and Rs are the same ordifferent and represent hydrogen or acyl radicals such as loweraliphatic acyl, halogen substituted lower aliphatic acyl, benzoyl,substituted benzoyl, araliphatic acyl and the like radicals. Byinspection of this general formula it will be appreciated by thoseskilled in the art that these products exist in one of twodiastereoisomeric or structural" forms depending upon the planarrelationship of the polar groups on the two asymmetric carbon atoms.Where the two most highly polar of the groups on the asymmetric carbonatoms lie on the same side of the plane of the two carbon atoms thecompounds are in the so-called "cis" or "regular form. Conversely. thecompounds wherein the two most highly polar groups lie on opposite sidesof the plane of the two carbon atoms are said to be in the trans" orpseudo structural 11 Claims. (CL 260-570.6)

2 form. Because of the difflculty' of representing these structuraldiflerences in graphic formulae the customary structural formulae willbe used herein and the structural or diastereoisomeric form of theproduct designated by the symbol "11 for the products having the transor pseudo configuration and the abbreviation reg." for the productshaving the "cis" or regular configuration.

In accordance with the invention (dl) -reg.

amino dlol derivatives of formula,

(dl)-reg.lorm

are converted to acid addition salts of (dl)-1,1 amino diols of formula,

w B1 OH NHg-HX oE-0morr nd iorm by treatment with ,a thionyl halidefollowed by hydrolysis of the intermediate product so formed, where R1,R2, Re, R; and Y have the same significance as given above. Acylrepresents an acyl radical such as a lower aliphatic acyl, a halogensubstituted lower aliphatic acyl, a benzoyl, a substituted benzoyl, anaraliphatic acyl and the like radicals and X is halogen. The amino diolcan be isolated from the reaction mixture either as the hydrohalide saltor, after neutralization of the salt, as the free base. Using thesymbols deilned above, these transformations may be diagrammaticallyillustrated as follows:

5 B1 0 \N n-pmoa. fi @-rr-cmom R: Y it:

(104' form )-i form 3 The first phase of the conversion, the reaction ofthe (dl) -reg. amino diol derivative with the thionyl halide, is carriedout below about 50 C. either in the presence or absence of asubstantially anhydrous, inert organic solvent such as benzene, toluene,xylene, chloroform, carbon tetrachloride and the like. In general, it ispreferable not to use any solvent other than an excess oi the thionylhalide. in this manner particularly good results are obtained by the useof about 4 to 6 parts by .weight When carrying out the reaction The (dl)-reg. amino diol derivatives used in the practice or the invention neednot be in the pure state and in fact one of the more importantapplications of the invention consists in converting a mixture composedoi the (dl) -reg. and (d1) -1p forms of an amino diol derivative into aproduct consisting solely of an acid addition salt or a (dl)-ill-aminb'did]. The (dl)-ill diastereoisomer present in the mixture used as thestarting material does not undergo any change in structuralconfiguration during the process of the h onyl halide for each. part byweighta; on NH-ecyl m The preferred into the (dl) -1p diastereoisomer.

while the (dl) -reg. diastereoisomer is converted Although the(dl)-'p-diastereoisomer does not undergo any change in structuralconfiguration during the process,.the acyl group present on the aminogroup and, if any, the acyl group on the primary alcohol group areremoved during the hydrolysis step with the result that a productconsisting solely of an acid addition salt of a (dl) at amino diol isobtained. This application of the invention can be diagrammaticallyillustrated as {01- lows:

Q-drr-tamo a. R: I":

(dl)-reg. iorm Postnlated integmediate i'or (dl)-reg.

31 on NYE-acyl o c1I-cm0n. B: in B1 0 0 6 tom (l-CH-lH: )i R| is\Q'H-acyl Hi0 H m B. on Nm-nx a. on NH:

c-on-cmon l tion cn-cmon B1 is R: A it:

' dl)-e iorm dl)-c form preferable to employ more than the minimalamount of water necessary for the hydrolysis but the exact amount is notcritical. Where a solvent has been employed in the first phase of thereaction it is preferable from the standpoint of simplicity in workingup the reaction mixture to carry out the hydrolysis step before removingthe solvent. The (dl) all-amino diol products can be isolated from thereaction mixture in a number of different ways. Where the organicacid(s) formed by hydrolysis of the acyl group(s) is volatile thehydrohalic acid addition' salt of the (dl) -1p-amino diol can beobtained by evaporation of the reaction mixture to dryness. Where theorganic acld(s) formed by the hydrolysis of the acyl gr0up(s) is notvolatile it can be removed from the reaction mixture by extraction witha water immiscible organic solvent and the hydrohalic acid addition saltof the (dl)- b-amlno diol recovered from the aqueous phase byevaporation. If desired, the free base of the (dl) b-amino diol can beobtained by neutralizing the acid addition salt present in the reactionmixture and separating the (dl)- b free base from the solution eitherfiltratidn or extraction.

possessing antibiotic activity.

Example 1 (a) 5 g. of (d1)-reg.-1-p-nitrophenyl-2-acetamidopropane-1,3-diol (M. P. 189-93 0.) isadded to 15 cc. of thionyl chloride at about 25 C. Hydrogen chloride isevolved and the solid dissolves with the production oi a light greensolution. The mixture is allowed to stand for fifteen minutes and thentreated with 15 cc. of water which causes vigorous gas evolution and amarked cooling of the mixture. The solution steam bath for about onehour.

5 is heated on a steam .bath for one hour, d colorized with charcoal andthe solution made alkaline with concentrated ammonium hydroxide. Thesolution'is cooled and the crystalline (dl)l-p-nitrophenyl-Z-aminopropane-lB-diol of forcollected;' M. P. l30-2 C.tion from hot water yields the pure free base melting at 137-8" C.

- Kb) 10 g. of (dl)-rem-l-nitrophenyl-Z-acet- 'amidopropane-Lii-diol isadded to 30 cc. of tliionyl chloride at 27 C.and the mixture almeltingat 170-2" The hydrochloride salt is dissolved in 35 cc. ofwaterfthesolution made alkaline to pH 10.with 10% sodium hydroxide solution andthe crystalline free base which separatestfrom thesolution collected.The (dl)- o-l p-nitrophenyl 2 aminopropane-lB-diol so obtained melts at133-5 C. before w w tionand after recrystallization from water at g. of(dl) -reg.-l-p-'nitrophenyl-2-acetamido-3-acetoxypropane-l-oliis addedto 15 cc.

of thionyl chloride at 25-7 Cxand solution allowed to stand for aboutfifteen minutes. 15 cc. ofwater' isadded cautiously to the reactionmixture and afterthevigorous reaction has subsided the. mixture isheated on a The solution is decolorized with charcoal and made alkalinewith concentrated ammonium. hydroxide. The solution is cooled and thecrystalline (dl) 4 -1- p-nitrophenyl-2-aminopropane- 1,3 diol whichseparates collected and'purifled by recrystallization from water; M. P.137-8 C.

.(d) A mixture consisting of 2 g. of (dl) -reg.-l-p-nitrophenyl-2-acetamidopropane 1,3 diol Iandl g. of (d1) -\l-l-p-n1trophenyl-2-acetamidopiopane-lB-diol is added to 9 cc.- ofthionyl chloride at about 25 c. -After about fifteen minutes 10 cc. ofwater isadded cautiously, the

mixture heated on a steam bath forftwo hours and then evaporatedtodryness. The residue which consists of the hydrochloride salt of (dl)-vp-l-p-nitrophenyl 2-aminopropane-1,3 v diol is dissolvedin a smallamount of water, the solution charcoaled and .then made alkaline withammonium hydroxide. The solution'is cooled and the crystalline (dl)l/-1-p-nitrophenyl-2- aminopropane-lB-diol which separates collected; M.P. 135-'l C. Recrystallization from water raises the melting point to137-8 C.

Example 2 (a) 5 g. of (dl) -reg.-1-phenyl-2- acetamidopropane-1.34101 isadded to cc. of thionyl chloride maintained at C. over a period offifteen minutes. Hydrogen chloride is evolved 6tendstorisednrlngtheaddition. Aftertheaddition has been completed thesolution is allowed to stand m1- fifteen to thirty minutes and then-80cc. of water is added cautiously. 'Theresulflngmixtureisheatedonasteambathfor 'onehourandevaporatedtodrynesstoobtain the hydrochloride salt of (dl)-w-l-phenyl-2-aminopropane-lfi-diol of formula, on mil-n01 Ocular-0 11,01!

Theproductinmanyinstancesisinthe form of-a light colored oil. Ifdesired, it may be converted' to the crystalline (dl) -1l/-1-phenyl-2-acemmidolfi-diacetoxypropane, M. P. 72-3 0., by treatment with aceticanhydride and pyridine followed by recrystallization from ethylacetatepetmletnnethermixture. w

. (b) 5 g. of (dl) -reg.-1-ph'enyl-2-acetamldo-3- acetoxypropaned-ol isadded to 15 cc. of thionyl bromide keeping the temperature at'25"- C.The resulting solution is allowed to stand-for fifteen minutes and then15 cc. of 'water'is added cautiously. The reaction mixture is heated ona steam bath for about one hour, cooled and made alkaline to pH 10 withsodium hydroxide solution. The mixture is extracted with ethyl acetateand the ethyl acetate extracts evaporated to dryness in vacuo to obtainthe desired (dl) 41-1.- phenyl-Z-aminopropane-lB-diol of formula,

Alternatively the reaction mixture can be evaporatedto dryness in vacuotoobtain the .hydrobromidesalt 0f (dl)--1-phenyl-2-aminopropane-1,3-dioL' I p 1 w (c) 5 g. of (dl)-reg.-l-phenyl-2-benzamidopropane-1,3-diol is added slowly to 15 cc. ofthionyl ,chloride keeping the temperature below 3 C- After-the additionits been completed the solutionis allowed to standfor fifteen and thencautiously treated with 25 cc. of water. is heatedon a steam bath forone hour, cooled and made: alkaline with 10 N hydroxide solution. Thesolution is with ethyl a cetate,the extracts dried and the ethyl acetatedistilled in vacuo to obp'ane-l,3 dioL Y same P duct can also. beobtained by suhstituting an equivalent amount of (dl) -reg.-1-phenyl-2-chloroacetamidopropane-13-diol for the benzamido derivativeused in the above procedure.

(d) A mixture consisting of 2 g. of (dl) -reg.-l-phenyl-z-acetamidopropane-lfi-diol and 1 g. of (dl)b-1-phenyl-2-acetamidopropane-1,3-diol is added to 9 cc. of thionylchloride keeping. the temperature at about 25 C. After solution iscomplete and the mixture has been allowed 'to stand for about fifteenminutes, 10 cc. of water is added cautiously and the mixture heated on asteam bath for about two hours. The reaction mixture is evaporated todrynessand the residue which consists of (dl)--1-phenyl-2-aminopropane-1,3-diol hydrochloride taken up in 2 cc. ofhot water. The solution is allowed to cool and the crystalline (dl)-1p-1-phenyl-2-aminopropane-1.34101 hydrochloride which separatesvigorously and the temperature of the solution 75 collected; M. P. 1'78C.

tain the. desired (dl)- b-1-phenyl-2-aminopro- A was isomer can .beobtained in the formoilts triquantity of (till-#1 acetate by evaporatingjthe aqueoussolutiod to .Tdryne'ss,'ti"eating it with acetic anhydndemdExample? phenyl-2-propionamidopropane-l,3-diol is;v added slowly'to 35cc. of thionylchloride keepingz-the temperature below about 30?. C.yAitertthe addition has been completed, '35 .cc. oi-;water is addedslowly and then the mixture--heated.for,. one -hour decolorized withcharcoal-and thersolution made alkaline with concentrated ammonium.Thesolutionis cooled andthe crystalline (dl) -11-.l-o-methyl-p-nitrophenyl -.2- aminopropane-L3- collected andrecrystallized from water.

(b) By substituting 10 g ot- (dl)-re8.-1-omethylphenyl- 8propionamidopropane-l,3-dio1 for the corresponding p-nitrocompound usedin the above procedure one obtains (dl) l 1-omethylphenyl-z-aminopropane-1;3diol. The sulfate salt oi'this productbeprepared by dissolving the free base in "water containing-anequivalent amount of sulfuric acid "and evaporating the solution invacuo.'

I :EzemDl f..

10 e; or y phenylacetamidopropane ig diof is adrie d" to 20 cc.otthionyl chloride-keeping the temperature below about so" 0. Jitter theaddition- "been completed, the mixture is allowed tartan-cm: a

short time and thenBO'cc. oi water added cautiously. The reactionmixture" is' lieated-on 'a steambath '-for' about h'oii'rlthe solutioii-de colorized with charcoal and extracted exhaustively with ether toremove the-phenylacetic acid. The aqueous solution is evaporatedto' invacuo to obtain the hydrochloride'salt of (dl) b-l-m-methoxyphenyl-2-aminopropane-L3-dlol which has formula I on rmrncl on rr onlon method1910M,

. -ifie lo P One. steam bath-The reactiommixturejs cooled,

p Example 5 15 g. 0! (dl) -reg.-1-.(3,4-dimethylphenyl) i2- acetamido-Zi-benzoxypropane- 1-01 is added slowly to cc. of thionyl chloride atabout 20 C. The mixture is allowed to stand foriifteen to thirty minutesand then 60 cc. of water added cautlously. The resulting mixture isheated on a steam bath for about an hour, cooled and extraotedexhaustively with ether to remove the benzoic acid and most. of theacetic acid formed by the hydrolysis. The aqueous solution is madealkaline with concentrated ammonium hydroxide a t e: x e ex a d. i h ethac t e y a et s mp eQ eQQI wthr acetate .distilled in vacuoto obtain-.the desired .10 as: (an has.mamas .nitrolstaayn.

2-acetamido-.1-acetoxybutane-3-ol;isyadded slowly torrid cc.- oi thionylbromide: keeping :thefttmperature in the neighborhood-of 25 C.Theresuiting mixture is allowed to stand for aboutfiiteen minutes-and..then-30-cc. 0f water is added cautiously. Thereaction mixture isheated on-a steam bath for-onehour; decolorized with charcoal and thesolutionmadealkaline with'concentrated ammonium; hydroxide. Thecrystalline (dl) t 3 --'(3'-chlor.o:.- 5'.-rnitropheny1) -2-.amino-butane-LS-diolwhieh separates from the cool .solution iscollected -It; has; the formula,

foe he." 4 tin-omen above procedure (d1)4 43 (3*,5'-dibhlorophenyl) "The(dl)"-reg.';acylamido diol andfacylamido acyloxy alcohol compounds usedas 'starting'materials in the practice of the present'inventiorr can be'prepared by the methods described in the, copending application of HarryM. Crooks, Jr. M.ildredC. Rebstock, J Ohn Controlilis and Quentin R.B'artz entitled Organic'Nitrogen Compounds and Methods of obtaining theSame bearing-Serial N01 15,264 andflied on March 16, 1948. This'applicatlon has matured into Patent N 0. 2,483,884. One of the methodsdescribed in said applicationfor the preparation of the (dl) -reg.acylamido'acyloxy alcohol compounds, involves diacylatin'g thecorresponding (dl) -reg. amino diol with an. acyl anhydride at about 70'C.' The (dl) -reg. acylamldo acyloxy alcohol compounds so obtained canbe converted to the corresponding (dl) -reg. acylamido diols byhydrolysis with one equivalent of alkali in cold aqueous acetonesolution. Where the desired starting material is an acylamido acyloxyalcohol compound wherein the acyl groups on the amino and alcoholradicals are difierent the corresponding (d1) -reg. acylamido diolcompound is acylated again with an acyl anhydride at about 70 C. Stillanother method for preparing the (dl) -reg. acylamido diol startingmaterials consists in reacting the free (d1) -reg. amino diol,

with an acyl halide or anhydride under aqueous R1 OH NHa-HX was. Hm R,is

(dl)-form where Y is a member of the class consisting of hydrogen andNo2, R1 and R2 are members of the class consisting of hydrogen, halogen,lower alkyl and lower alkoxy radicals, Ra is a member of the classconsisting of hydrogen and lower alkyl radicals, R4 is a member of theclass consisting of hydrogen and acyl radicals and X is halogen.

2. Process which comprises reacting a thionyl halide with a (d1)-reg.-amino diol derivative of formula,

R1 OH NBC-acyl t-- HCH: in

(dl)-reg. form at a temperature below about 50 C. under substantiallyanhydrous conditions and thereafter hydrolyzing the intermediate productso formed with water at a temperature between about 60 and 110 C. toobtain an acid addition salt of (d1) -\l amino diol of formula,

on NHrHX De i-0114x1101; R: R:

(d1) 4 form where Y is a. member of the class consisting of hydrogen and-NO2, R1 and R: are members of the class consisting of hydrogen,halogen, loweralkyl and lower alkoxy radicals, R: is a member of theclass consisting of hydrogen and lower alkyl radicals, R4 is a member ofthe class consisting of hydrogen and acyl radicals and X is halogen.

3. Process which comprises reacting thionyl chloride with a (d1) -reg.amino diol derivative of formula,

at a temperature below about 50 C. under substantially anhydrousconditions and thereafter hydrolyzing the intermediate product soformed.

10 with water at a temperature between about 60 and 110 C. to obtain ahydrochloride salt of a (d1) ll-amino diol of formula,

RI 0H NHrHOl C- H-CHiOH R1 I l (db-d iorm where Y is a member of classconsisting of hydrogen and NO2, R1 and R; are members of the classconsisting of hydrogen, holagen, lower alkyl and lower alkoxy radicals,R: is a member of the class consisting of hydrogen and lower alkylradicals and R4 is a member of the class consisting of hydrogen and acylradicals.

4. Process which comprises reacting a thionyl halide with a (d1) -reg.amino diol derivative of formula,

OH NH-acyl NOrO-H-JJH-CIBOH (dB-reg. form at a temperature below aboutC. under substantially anhydrous conditions and thereafter hydrolyzingthe intermediate product so formed with water at a temperature betweenabout and C. to obtain an acid addition salt of a 9. (d1) -/-amino diolof formula,

OH NHa-HX where x is halogen.

5. Processv which comprises reacting a thionyl halide with 9. (d1)-reg.-amino diol derivative of formula,

OH NH-acyl (d1) -reg. form at a temperature below about 50 C. undersubstantiallyanhydrous conditions and thereafter hydrolyzing theintermediate product so formed with water at a temperature between about60 and 110 C. to obtain an acid addition salt of a (d1) al -amino diolof formula,

on Nm nx (dB-41 form where X is halogen.

6. Process which comprises reacting a thionyl halide with a (d1) -reg.amino diol derivative of formula,

0 H N H-acyl (d1) -reg. form at a temperature below about 50 C. undersubstantially anhydrous conditions and thereafter hydrolyzing theintermediate product so formed with water at a temperature between about60 and 110 C. to obtain an acid addition salt of a (d1) --amino diol offormula,

(dbiv form where x is a halogen atom.

R1 011 NE-acyl @d-drmomom B. It:

with a thionyl halide and hydrolyzing the reaction product therebyobtaining an acid addition salt of a (dl) n11 amino diol of formula,

RI OH mu 7 Ja-dn-omoa l)-Hm where Y is a member of the class consistingof hydrogen and -N02, R1 and R: are members of the class consisting ofhydrogen, halogen, lower alkyl and lower alkoxy radicals, R: is a memberof the class consisting .of hydrogen and lower alkyl radicals, R4 is amember of the class consisting of hydrogen and acyl radicals and X ishalogen.

8. Process which comprises reacting a mixture consisting of the (dl) and(dl) -reg. forms of an amino diol derivative of formula,

12, on NH-acyl R: on NHrHCl o cn-on.on

( )-v! form where Y is a member of the class consisting of hydrogen and--NO:, R1 and Rs are members of the class consisting of hydrogen,halogen, lower alkyl and lower alkoxy radicals, R: is a member of theclass consisting of hydrogen and lower alkyl radicals and R4 is a memberof the class consisting of hydrogen and acyl radicals.

aturebetweenabontfilandllo'atoobtama ydrochloride salt of'a (dl)-94min!)diol of formula,

on run-n01 NOI-O-AK-(SHBaOH 10. Process which comprises reacting a (dl)-reg. amino diolderivativeoffonnula.

0 0K IVE-L030 0 NOOlIL-lH-Olh O-OH;

I arm-Qcnwa-cmon l)-i Inn 11. A process which comprises reacting a (dl)reg. amino diol derivative of formula.

0 0B Nil-Lona with thionyl chloride at a temperature below 9. A processwhich comprises reacting a (dl)- reg. amino diol derivative of formula,

0 on Nn-a-cm NoOon-dH-cmon Dm-lm with thionyl chloride at a temperaturebelow about C. under substantially anhydrous conditions and thereafterhydrolyzing the intermediate product so formed with water at atemperabout 50 C. under substantially anhydrous conditions andthereafter hydrolysing the intermediate product so formed with water ata temperature between about and C. to obtain a hydrochloride salt of a(dl) -'p-amino diol of formula,

Ocular-omen )-i lmn GEORGE W. MOERSCH. ALLEN C. MOORE.

REFERENCES CITED The following references are of record in the flle ofthis patent:

nun-an s'r'a'ras PATENTS Chemistry and 00., Boston, 1944), pages278-280.

1. PROCESS WHICH COMPRISES REACTING A THIONYL HALIDE WITH A (DL)-REG.AMINO DIOL DERIVATIVE OF FORMULA,